By Aseel Rabadi
Title: Neurofibromatosis type 1
Author: Shahed Aldalahmeh
Editor: Aseel Rabadi, Sadeen Eid
Reviewer: Neebal Algallab, Ethar Hazaimeh
Keywords: Neurofibromatosis, Neurocutaneous syndromes
Overview
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, also known as Von Recklinghausen disease (VRD) or Peripheral Neurofibromatosis [1]. It significantly impacts the nervous system, eyes, skin, and bones. Affected individuals develop both benign and malignant tumors such as neurofibromas, malignant peripheral nerve sheath tumors, and gliomas. It has a prevalence of 1/3,000 and it is higher in young children than adults [2]. It has one of the highest mutation rates in humankind [3].
Risk Factors
NF1 affects both sexes and all races and ethnic groups [53]. The most important risk factor is having one of the parents with the same condition because it’s AD, so any child of an affected individual has a 50% chance of getting this disease.
Etiology and pathogenesis
Neurofibromatosis type 1 (NF1) results from mutations in the NF1 gene and shows approximately complete penetrance, although the expressivity is highly variable, even among other family members with the same mutation [4,5]. This point is essential for genetic counseling because a patient with mild clinical manifestations can have a child with a more severe phenotype, or vice versa.
The NF1 gene encodes Neurofibromin, located on chromosome 17, band q11.2, which is a large and complex gene, that carries more than 280 kb of genomic DNA, including 57 constitutive exons and other alternatively spliced exons [6].
Neurofibromin is considered a negative regulator of RAS signaling (the RAS proteins control many cellular processes such as cell proliferation, cell differentiation, cell migration, and apoptosis. Ras and Ras-related proteins are mostly deregulated in cancers, leading to increased invasion and metastasis of the tumors, and decreased apoptosis of the cancerous cells [7]), and are also expressed in the migrating trunk and cranial NC cells during early fetal development [8]. RAS requires Guanosine-5′-triphosphate (GTP) binding to stimulate the mitogen-activated protein kinase (MAPK) pathway, that initiates cell proliferation. Neurofibromin acts as a tumor suppressor that diminishes the activity of RAS by increasing the hydrolysis of GTP to GDP. Loss-of-function mutations in the NF1 gene lead to a predisposition for tumorigenesis as a consequence of improper activation of the RAS-MAPK pathway [9].
Clinical presentation
A number of the principles of human genetics are clearly conspicuous in NF1. These include penetrance, variable clinical expressivity, pleiotropy, mosaicism, age-dependent expression of clinical manifestations, somatic mutation, and locus heterogeneity which makes the clinical manifestations of NF1 variable, unpredictable, and age-related [10]. Moreover, complications can occur in any of the body systems in tissues of ectodermal, mesodermal, and neural tube origin making the clinical manifestation wide and miscellaneous [11].
Common clinical NF1-related manifestations based on the NIH diagnosis criteria:
Figure 1 Common affected systems and related phenotypes in neurofibromatosis type 1 (NF1) patients. Diverse clinical features present due to the NF1 gene mutations in different cell types including melanocytes, neurons, neuroglial cells, osteoblasts, etc. (A) Lisch nodules, (B) cafe-au-lait macules, (C) cutaneous neurofibromas, (D) plexiform neurofibromas, (E, F) gliomas, (G) scoliosis, (H) pseudoarthrosis. Images are used with the patient’s permission. [4]
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Cafe-au-lait macules
CALMs are recognized as the most common pigmentary feature of NF1 caused by biallelic loss of NF1 in melanocytes and they are an early feature of NF1, with great diagnostic importance in children [12]. They are sometimes present at birth or develop between early infancy and 2 years of age [13].
Although CALMs are found in other genetic conditions such as Legius syndrome [14], Noonan syndrome [15], constitutional mismatch repair deficiency syndrome [16], and ring chromosomes [17], CALMs are not a cardinal feature of these conditions [18].
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Lisch nodules (iris hamartoma)
Lisch nodules are typical pigment features in NF1 diagnosis and the most common ocular manifestation of NF1 [19]. They are benign tumors located on the iris surface and present well-defined, gelatinous pigments and dome-shaped elevations of the iris surface. Apart from their advantage in diagnosis, they have no known clinical consequences [20]. It is arguable whether the Lisch nodule burden predicts the cutaneous severity in NF1 or not [21].
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Cutaneous Neurofibromas (CNFs)
CNFs, also called dermal neurofibromas, strictly grow within the cutaneous dermis layer and form hundreds to thousands of small tumors all over the body. As a consequence, mobility and daily activities such as showering, sitting, or being confronted in public can be a serious burden for the patients. Nevertheless, they show no tendency to malignancy [22].
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Plexiform Neurofibromas (PNFs)
PNFs are benign nerve sheath tumors that occur commonly in individuals with (NF1) [23]. 20%-50% of NF1 patients present with PNFs [24]. PNFs are congenital and grow slowly, except in early childhood and pregnancy [25]. They arise within nerves and consist of several cell types, including Schwann cells, fibroblasts, perineural cells, mast cells, and macrophages [26]. The size and site of the tumor range determine the patients’ main complaints, which include facial defects, nearby-organ compression, deformities, or invasion and may further lead to physical pain and functional damage [27].
A recent study shows that patients with NF1 and PNFs had a higher mortality rate (5/154) when compared with patients without or with asymptomatic PNFs (2/366) [28]. PNFs can turn into Malignant Peripheral Nerve Sheath Tumors (MPNSTs) with a lifetime risk of 8-13% [29].
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Optic pathway tumors
These slow-growing tumors arise from glial cells that commonly involve the optic nerve and manifest in patients with NF1 with a percentage of 5-25% [30]. These tumors can affect a single optic nerve or both nerves affecting the optic chiasm [32]. Tumors in children can grow outside the visual pathway causing headaches, cranial neuropathies, and other neurological problems [31]. The location of the tumor determines the presenting symptoms, patients might have visual field defects, achromatopsia, and decreased clearness of vision [33].
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Osseous Lesions
Numerous studies have revealed that 50% of NF1 patients exhibit orthopedic symptoms, such as scoliosis, osteoporosis, deformities in the skull, tibial dysplasia, and pseudoarthrosis, as well as a decrease in muscle strength [34]. Muscle dystrophy caused by Nf1 gene inactivation is characterized by fibrosis, a decrease in the number of muscle fibers, and a decrease in muscular force [35].
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Epilepsy
There appears to be about a tenfold increase in the probability of developing seizures in NF1 compared with the general population and this might be due to the inactivation of neurofibromin [36], NF1-related epilepsy may be linked with underlying cortical dysgenesis and a pathology study of patients with NF1 and cognitive impairment revealed abnormal cerebral architecture, subcortical heterotopias, and glial nodules [37]. Moreover, it is found that neurofibromin has a role in central nervous system formation, and loss of Nf1 function in neurons of transgenic mice results in astrogliosis and hippocampal dysplasia [38].
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Cerebrovascular disease
Cerebrovascular disease is a serious manifestation of NF1 and appears in children as stenosis or occlusion of the internal carotid, middle cerebral and anterior cerebral arteries, moyamoya disease, and aneurysm formation [37].
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Gastrointestinal complications
There is a chance of developing a gastrointestinal stromal tumor (GIST), a mesenchymal neoplasm that is detected mainly in the small bowel, and causes gastrointestinal bleeding and anemia [39]. Inactivation of the wild-type NF1 allele is demonstrated in the tumor with increased MAP kinase signaling, but NF1 GIST doesn’t display other molecular changes that are present in sporadic GIST [40]. Carcinoid tumors have been reported in NF1 patients and sometimes occur with pheochromocytoma [41]. The presenting symptoms are jaundice, weight loss, anemia, or bleeding. NF1 carcinoid tumors are located mostly in the duodenum; surgery is the first option for treatment and the prognosis is usually good [42].
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Cognitive impairment
NF1 is characterized by frequent occurrence of cognitive impairment that manifests as a low IQ, specific learning difficulties, and behavioral problems [43]. Impaired visual-spatial ability, poor fine motor skills, reading and writing difficulties, reduced nonverbal long-term memory, attention deficit, and executive function problems have been observed and affect about 60% of patients with NF1 [44].
Diagnosis
The National Institutes of Health (NIH) Consensus Development Conference 1988 developed the diagnostic criteria for NF1. The diagnosis is based on clinical assessment where two or more of the following features are required to be diagnosed with NF1 [45,41]
- 6 or more café au lait macules (>0.5 cm in children or >1.5 cm in adults)
- 2 or more cutaneous/subcutaneous neurofibromas or one plexiform neurofibroma
- Axillary or groin freckling
- Optic pathway glioma
- 2 or more Lisch nodules (iris hamartomas seen on slit lamp examination)
- Bony dysplasia (sphenoid wing dysplasia, bowing of long bone ± pseudarthrosis)
- First-degree relative with NF1
NF1 should be distinguished from other forms of neurofibromatosis and overgrowth syndromes, from tumors that may be confused with neurofibromas, and from conditions with pigment abnormalities [46].
Other forms of neurofibromatosis[41]
- Segmental/mosaic NF1
- Watson syndrome
- Autosomal dominant multiple café au lait patches alone (some allelic with NF1)
- Neurofibromatosis 2
- Schwannomatosis
Other conditions with café au lait patches
- McCune–Albright syndrome
- DNA repair syndromes
- Homozygosity for one of the genes that cause hereditary non‐polyposis cancer of the colon.
Conditions with pigmented macules confused with NF1
- LEOPARD syndrome
- Neurocutaneous melanosis
- Peutz–Jeghers syndrome
- Piebaldism
Localized overgrowth syndromes
- Klippel–Trenauny–Weber syndrome
Treatment
NF1 currently has no known treatment. Regular monitoring and solving the problem are part of the treatment process. The goal of treatment for malignant peripheral nerve sheath tumors (MPNSTs) is to completely remove the tumor; radiotherapy is advised for high-grade and incompletely removed tumors, and chemotherapy with doxorubicin and ifosfamide is given for metastatic disease or to shrink a tumor before surgery [47].
In plexiform and subcutaneous tumors, the tumors are hypercellular with atypical nuclei, but mitotic activity is low or absent [48]. Undoubtedly some tumors exhibit benign, atypical, and malignant features within the same lesion suggesting that some atypical neurofibromas have malignant potential. The current management is the removal of the neurofibroma and clinical follow-up for 5 years [49].
Café au lait macules are treated with surgical excision or laser therapy if treatment is desired [50].
Patients with NF1 are advised to have annual eye exams to check for optic pathway tumors and monitor for visual acuity, visual fields, and color vision [51], chemotherapy can be used to treat progressive optic pathway tumors that cause visual loss [52]. While radiotherapy is an alternative, it is typically not advised for very young infants due to the risk of major neurologic problems and potential secondary cancers brought on by radiation [41]. Optic pathway glioma removal surgically is also not advised since it is not practical and may cause further visual morbidity.
Prevention
Unfortunately, there’s no medical treatment that can prevent or reverse the manifestations of NF1. Instead, medical management is focused on the early detection of treatable complications and prompt institution of appropriate therapy [53].
The prognosis
Due to the wide variety of expressions, it is hard to make a general statement about the prognosis so it depends on the severity of the patient`s condition [53].
References...
